ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.212+3A>G (rs80358083)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000083178 SCV000244314 pathogenic Breast-ovarian cancer, familial 1 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000083178 SCV000325243 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506191 SCV000602702 pathogenic not specified 2016-11-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509906 SCV000607764 pathogenic Hereditary cancer-predisposing syndrome 2018-12-07 criteria provided, single submitter clinical testing The c.212+3A>G intronic pathogenic mutation (also known as IVS5+3A>G) results from an A to G substitution 3 nucleotides after coding exon 3 in the BRCA1 gene. This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: segregation with disease, mutation co-occurrence, and family history (Easton DF. Am. J. Hum. Genet. 2007 Nov; 81(5):873-83; Lindor NM. Hum. Mutat. 2012 Jan; 33(1):8-21). Although one study utilizing RT-PCR on patient RNA found no effect on normal splicing (Chen X. Hum. Mutat. 2006 May; 27(5):427-35), multiple mini-gene assays have observed that this alteration creates a splicing defect by reducing the affinity of the native donor site, activating a cryptic exonic donor site 22 nucleotides upstream from the native site, leading to a frameshift and premature stop codon (Houdayer C. Hum. Mutat. 2012 Aug; 33(8):1228-38; Théry JC. Eur. J. Hum. Genet. 2011 Oct; 19(10):1052-8; Steffensen AY. Eur. J. Hum. Genet. 2014 Dec; 22(12):1362-8; Sanz DJ. Clin. Cancer Res. 2010 Mar; 16(6):1957-67). Steffensen and Sanz also found transcripts with in-frame skipping of coding exon 3. In one study, the predictions of an in silico splice prediction model were concordant with these published findings (Mucaki EJ. Hum. Mutat. 2013 Apr; 34(4):557-65). This mutation has been detected in multiple breast and/or ovarian cancer families and is a known Belgian founder mutation, though it has also been reported in German, Dutch, and French families to date (Peelen T. Am. J. Hum. Genet. 1997 May; 60(5):1041-9; Claes K. Br. J. Cancer 2004 Mar; 90(6):1244-51; Claes K. Dis. Markers 1999 Oct; 15(1-3):69-73; Janavičius R. EPMA J 2010 Sep; 1(3):397-412). Based on the available evidence, c.212+3A>G is classified as a pathogenic mutation.
Invitae RCV000496318 SCV001589172 pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-04 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant is a well known cause of breast and ovarian cancer in Belgium, although it has been also observed in other populations (PMID: 10595255, 15026808, 9150151, 10090482, 16619214, 28294317). This variant is also known as IVS5+3A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 54467). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 21990134). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change inactivates the intron 5 natural donor splice, leading the skipping of exon 5 or the activation of a cryptic donor splice site 22 nucleotides upstream (PMID: 12037674, 21673748, 24667779, 29021971). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000083178 SCV000115252 pathogenic Breast-ovarian cancer, familial 1 2010-02-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083178 SCV000144666 not provided Breast-ovarian cancer, familial 1 no assertion provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496318 SCV000587034 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735529 SCV000863667 uncertain significance Breast and/or ovarian cancer 2015-04-09 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000083178 SCV001238071 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355367 SCV001550239 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 c.212+3A>G variant was identified in 2 of 1942 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Chen 2006, Kwong 2018). The variant was also identified in dbSNP (ID: rs80358083) as ""With Pathogenic allele"", ClinVar (classified as pathogenic by five submitters; as likely pathogenic by one submitter and uncertain significance by one submitter) and in LOVD 3.0 (99X as pathogenic). The variant was identified in control databases in 1 of 30976 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 15010 chromosomes (freq:0.00007), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, Finnish, South Asian, African or East Asian populations. The c.212+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. Multiple splicing assay studies using RT-PCR analysis on RNA identify the variant causing in-frame skipping of exon 5 and out-of-frame skipping of the last 22 nucleotides of exon 5 (Houdayer 2012, Steffensen 2014, Thery 2011). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001528962 SCV001741619 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001528962 SCV001959047 pathogenic not provided no assertion criteria provided clinical testing

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